Novel particles for image-guided cancer therapy

Abstract

Although great progress has been made during the last decades to overcome cancer, this disease still remains one of the leading causes of death worldwide. A promising development in cancer research is targeted therapy, where tumors are treated locally, thereby preventing damage to the surrounding healthy tissue. Local therapy can be achieved in different ways. For example, nanocarriers can be loaded with chemotherapeutic compounds and systemically administered into the blood stream. By encapsulation of the drugs in these carriers, their solubility, stability and pharmacokinetic properties can be improved. Furthermore, microparticles offer excellent opportunities for targeted drug delivery. Embolotherapy involves the administration of microparticles with a size between 15 – 1200 µm into the tumor-feeding artery by catheterization. The microspheres lodge in the tumor-feeding artery and thereby block the blood flow, causing a lack of nutrient and oxygen supply to the tumor which finally leads to necrosis of the tumor tissue. Beside targeted therapy with nano- and microparticles, local tumor therapy can also be achieved by external modalities, such as high-intensity focused ultrasound (HIFU), which enables accurate ablation of malignant tissue. Next to tumor ablation, HIFU is also able to trigger drug release from nanocarriers such as polymeric micelles and liposomes to improve treatment outcome. In this dissertation, it is shown that an additional mechanism, opposed to temperature elevation or cavitation, two commonly known effects of HIFU exposure, is responsible for the release of both hydrophilic and lipophilic compounds. The release most likely originates from radiation force-induced acoustic streaming, resulting in shear forces causing reversible destabilization of the nanoparticles and subsequently release of the loaded compounds. This new release mechanism could mean a paradigm shift in HIFU-triggered drug release which brings the field of triggered drug release a major step forward. Beside novel nanoparticles, this thesis describes the development and characterization of microspheres which can be visualized with multimodality medical imaging techniques, such as magnetic resonance imaging (MRI), and X-ray imaging techniques like fluoroscopy and computed tomography (CT). The microspheres could even be depicted as individual beads, allowing precise quantification of the administered dose. The combination of intra-procedural visualization, multimodality imaging for patient follow-up and the possibility of quantification offers a new and promising method for more safe, efficient and successful embolotherapy. The particles as described in this dissertation can be tailored in various ways, enabling the development of personalized medicine where the therapy can be adjusted to the needs of the individual patient. For these combined therapies, the main focus is to design imageable drug delivery systems, which also allow drug release ‘on command’, resulting in a high efficacy with a significant decrease in toxicity and side effects. Merging the platforms of nano- and microparticle-based drug delivery combined with triggered drug release and multimodality imaging facilitates interdisciplinary integration of both preclinical and clinical research and brings the prospect of the ‘magic bullet’ a major step forward